Clinical Trials Guide
They form the basis of evidence-based medicine but remain uncommon within the surgical specialties. This is in part due to the nature of surgical interventions but also due to a lack of experience amongst surgeons.
This page uses an example to illustrate the steps involved in planning, executing and analysing a clinical trial. Our example clinical trial will compare dressing A with dressing B for the treatment of a leg ulcer.
The research question
All clinical trials start with a good idea. The question needs to be clinically relevant and possible to answer. This should be backed by a literature review and discussion with relevant experts to ensure that it is worth pursuing.
In this example, we will compare our standard dressing A with another product, dressing B. Dressing B apparently contains new technology that improves wound healing. Our initial hypothesis is that dressing B will heal leg ulcers faster than dressing A.
First, we find out more about the dressings. The manufacturer’s websites should provide data sheets and a literature review will help us write a brief project proposal and determine whether the project is worth pursuing. Discussion with consultant colleagues and local experts can help in this process. It is worth checking the clinicaltrials.gov website to see if a similar trial is already underway.
Consider the following questions:
• What is published on the healing properties of both dressings?
• What are their biological properties?
• Why might dressing B offer an advantage over dressing A?
• Are they safe?
• Has a similar clinical trial been performed? If so, was the design adequate?
• What should we use as our primary end points?
At this point, summarise your ideas in a brief project proposal (side of A4):
Introduction: Background to the project and review of key literature.
Hypothesis: Primary aim of project
Methodology: Single v multicentred; randomisation; intervention protocol; patient recruitment (inclusion / exclusion criteria); power calculation; statistical methodology, “blinding” of groups for analysis.
Outcome measures: Endpoints for the data collection i.e. healed wound
Initiate contact with your local NHS or University Research and Development (R&D) department. They will provide additional help and guidance. It is also worth contacting your local Clinical Trials Unit (CTU) as they will be able to offer useful information. The Royal College of Surgeons has recently funded five CTUs to promote surgical research. At the time of writing these are in Oxford, Bristol, Liverpool/Manchester, Birmingham and London (St Barts and the Royal London). The Royal College has also appointed a Surgical Speciality Lead for Plastic Surgery who can also offer support.
We have started to develop a study design in the form of a project proposal. This needs to be fleshed out and will culminate in a formal document that is completed online using the Integrated Research Application System (IRAS). The study will need to be registered (see below).
IRAS (www.myresearchproject.org.uk) has an e-learning module to guide you through the process of creating your trial protocol and submitting it to the relevant authorities. It is useful for funding and ethics approval if patients have been involved in the design of the study.
Funding sources should be considered early in the planning stage. Sources in the UK include the Medical Research Council (MRC), National Institute for Health Research (NIHR) and charities, e.g. Wellcome Trust and your local hospital. You could also approach the dressing manufacturer at the early stage but it is important that they have no influence in the data analysis as this could be seen as a conflict of interest.
Before obtaining funding for a full-scale trial it may be better to run a feasibility pilot study, which will help test your hypothesis and make a large grant application more robust. It is often easier to obtain funding for these smaller single centre studies. The aim of any clinical trial is to obtain NIHR funding/adoption, which will help immensely with infrastructure, support and funding. Factors that will help you get your study adopted by the NIHR include a testable hypothesis, statistical validity, adequate protocol review, the ability to deliver the study on time, sufficient patients, investigator interest and that your study does not conflict with trials already on the portfolio.
Trials are led by the Chief Investigator, usually a healthcare professional. In this study, it would be the lead consultant plastic surgeon supervising the project. If the study is to be undertaken as part of an MSc or PhD IRAS recommend that the student should be on the ethics paper work. A sponsor is required for every trial. This is usually an organisation, in our case an NHS trust, but it is frequently a university. The sponsor takes responsibility for managing the trial and providing indemnity.
Submission for approvals
Various approvals are required before starting a trial. These are gained through submission of the IRAS form to the relevant organisations such as the local research ethics committee, R&D department and Medicines and Healthcare Products Regulatory Agency (MHRA). In this instance, both dressing A and dressing B are on the market, have CE approval and are being used for their intended purpose. Therefore the MHRA does not need to be notified. Check out the MHRA website for more information about trialling new medical devices or medicines.
All clinical trials require submission of a Clinical Trial Authorisation application to a competent authority. European trials, including the UK, are given an EudraCT reference number. In the USA, ClinicalTrials.gov manages trial registration. In addition, the World Health Organization maintains an International Clinical Trials Registry Platform (ICTRP) to collate information from the Primary Registries around the world meeting the requirements of the International Committee of Medical Journal Editors (ICMJE).
It is a requirement for anyone involved in the conduct of a clinical trial to have completed the Good Clinical Practice course. This can be done as a taught course or as e-learning
Subject recruitment starts once the trial is approved and registered. During the trial update your collaborators with progress reports and try and maintain enthusiasm for patient recruitment. If the trial has been adopted by the NIHR portfolio (most patient trials will be), one is required to provide month recruitment accrual information using an online portal. This is important as studies that are ‘under-recruited’ or who are not reporting recruitment will prevent the hospital/local CRN from getting reimbursement (which could pay for a research nurse etc.)
Patient safety is paramount at all times and so once underway there are statutory requirements for monitoring of the trial and reporting of adverse events. Trial amendments need to be resubmitted to the relevant authorities. Once completed an End of Trial Declaration is submitted and the trial database locked.
Analysis and Reporting
Data analysis should follow the trial protocol and be supervised by a qualified statistician. There are usually reporting targets following the end of the trial. Publication of trial data should follow the CONSORT guidelines; most journal editors have adopted these.
The trial data will need to be archived, usually the local R&D department can help you with finding a suitable repository.
Clincal Trial Authorisation- CTA from the MHRA is required for all clinical trials in the UK within the scope of UK regulation
Clinical trials toolkit- Joint development by the Department of Health and the Medical Research Council to provide information on the Medicines for Human Use (Clinical Trials) Regulations 2004.
EudraCT- Database of clinical trials in the European Community from 2004 onwards
EudraPharm- Database of all medicinal products for human or veterinary use that have been authorised in the EU and the EEA and information on clinical trials of medicinal products including products with or without a marketing authorisation
Declaration of Helsinki- Ethical Principles for Medical Research Involving Human Subjects first published by the World Medical Association in 1964 and updated in subsequent years.
Good Clinical Practice (GCP)- The European Union Clinical Trials Directive dictates clinical trials follow the principles of Good Clinical Practice. These are specified in the EU Commission Directive on GCP. This has been incorporated into the Medicines for Human Use (Clinical Trials) Regulations 2004.
Health Research Authority (HRA)- NHS organisation that now administers the NRES. It functions to protect and promote the interests of patients and public in health research
Integrated Research Application System (IRAS)- Single system for applying for the permissions and approvals for health research in the UK. It is the recognised format for a number of organisations
International Conference on Harmonisation (ICH)- Brings together the drug regulatory authorities and the pharmaceutical industry of Europe, Japan and the United States.
Medicines and Healthcare Products Regulatory Agency (MHRA)- UK government agency responsible for ensuring that medicines and medical devices work and are acceptably safe.
Regulatory Support Centre- Hosted by the Medical Research Council (UK), it provides support for investigators undertaking clinical trials
UK Clinical research Collaboration (UKCRC)- Brings together many partners to foster high quality clinical research